U.S. patent application number 13/749592 was filed with the patent office on 2013-10-10 for (1r,4r) 7-oxo-2-azabicyclo[2.2.2]oct-5-ene and derivatives thereof.
The applicant listed for this patent is DemeRx, Inc.. Invention is credited to Robert M. Moriarty.
Application Number | 20130267710 13/749592 |
Document ID | / |
Family ID | 48873876 |
Filed Date | 2013-10-10 |
United States Patent
Application |
20130267710 |
Kind Code |
A1 |
Moriarty; Robert M. |
October 10, 2013 |
(1R,4R) 7-OXO-2-AZABICYCLO[2.2.2]OCT-5-ENE AND DERIVATIVES
THEREOF
Abstract
This invention provides novel (1R,4R)
7-oxo-2-azabicyclo[2.2.2]oct-5-ene and derivatives thereof,
preferably in substantially enantiomerically enriched forms,
intermediates thereto, and processes of their synthesis.
Inventors: |
Moriarty; Robert M.;
(Michiana Shores, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DemeRx, Inc. |
Miami |
FL |
US |
|
|
Family ID: |
48873876 |
Appl. No.: |
13/749592 |
Filed: |
January 24, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61741798 |
Jan 25, 2012 |
|
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Current U.S.
Class: |
546/18 ; 546/112;
546/183 |
Current CPC
Class: |
C07D 491/20 20130101;
A61K 31/46 20130101; C07D 471/08 20130101; C07D 493/20 20130101;
C07D 495/20 20130101; C07D 453/06 20130101 |
Class at
Publication: |
546/18 ; 546/183;
546/112 |
International
Class: |
C07D 471/08 20060101
C07D471/08; C07D 493/20 20060101 C07D493/20; C07D 495/20 20060101
C07D495/20 |
Claims
1. A compound of Formula (I) or (Ia): ##STR00026## or a salt
thereof wherein, R.sup.1 is selected from the group consisting of
hydrogen, --CO.sub.2R.sup.11, --COR.sup.12, --C(R.sup.13).sub.3 ,
and an amine protecting group; R.sup.11 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
substituents selected from C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6
alkoxy, silyl, nitro, cyano, and CO.sub.2H or an ester thereof,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and
C.sub.3-C.sub.8 heterocyclyl, R.sup.12 and R.sup.13 independently
are selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl optionally substituted with 1-3 substituents selected from
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3,
hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H
or an ester thereof, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10 heteroaryl,
C.sub.3-C.sub.8 cycloalkyl, and C.sub.3-C.sub.8 heterocyclyl,
R.sup.2 and R.sup.3 independently are hydrogen, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl, --SR.sup.21 or --OR.sup.22, wherein the alkyl, alkenyl, or
the alkynyl group is optionally substituted with 1-3 substituents
selected from the group consisting of keto, halo, C.sub.1-C.sub.6
alkoxy, amino, hydroxy, cyano, nitro, --NHCOCH.sub.3, --N.sub.3,
and --CO.sub.2H or an ester thereof, provided that at least one of
R.sup.2 and R.sup.3, preferably R.sup.2 is a non-hydrogen
substituent, or R.sup.2 and R.sup.3 together with the carbon atom
to which they are bonded to form a keto (C.dbd.O) group, a Schiff's
base (.dbd.NR.sup.24), a vinylidene moiety of formula
.dbd.CR.sup.25 R.sup.26, or form a 5-6 membered cyclic ketal or
thioketal, which cyclic ketal or thioketal of formula: ##STR00027##
each R.sup.21 is independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
substituents selected from C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6
alkoxy, silyl, nitro, cyano, and CO.sub.2H or an ester thereof,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and
C.sub.3-C.sub.8 heterocyclyl; each R.sup.22 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl
optionally substituted with 1-3 substituents selected from the
group consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6
alkoxy, silyl, nitro, cyano, and CO.sub.2H or an ester thereof,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl; X in both
occurrences is either oxygen or sulfur; m is 1, 2, 3, or 4; n is 1
or 2; R.sup.23 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; R.sup.24 is
selected from the group consisting of C.sub.6-C.sub.10 aryl and
C.sub.2-C.sub.10 heteroaryl; R.sup.25 is hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl,
wherein the alkyl, alkenyl, or the alkynyl group is optionally
substituted with 1-3 substituents selected from the group
consisting of keto, C.sub.1-C.sub.6 alkoxy, amino, hydroxy, cyano,
nitro, --NHCOCH.sub.3, and --CO.sub.2H or an ester thereof;
R.sup.26 is hydrogen or C.sub.1-C.sub.6 alkyl; R.sup.4 and R.sup.5
independently are selected from the group consisting of hydrogen,
halo, C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
substituents selected from the group consisting of C.sub.6-C.sub.10
aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10 heteroaryl,
C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3, hydroxy,
C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, vinyl, ethynyl, and
CO.sub.2H or an ester thereof, R.sup.6 is selected from the group
consisting of --O--, --NH--, and --NR.sup.61; R.sup.61 is selected
from the group consisting of hydrogen and an amine protecting
group; the amine protecting group is selected from the group
consisting of --CO.sub.2CMe.sub.3, --CO.sub.2Bn, --CO.sub.2-allyl,
--Fmoc (flurenyloxymethyl), --COCF.sub.3, Bn(CH.sub.2Ph),
--CHPh.sub.2, and --CPh.sub.3; wherein the cycloalkyl,
heterocyclyl, aryl, or heteroaryl, is optionally substituted with
1-3 substituents selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 aryl, cycloalkyl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3,
hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H
or an ester thereof.
2. The compound of claim 1, of Formula (II): ##STR00028## wherein
R.sup.1, R.sup.2, and R.sup.3 are defined as in claim 1.
3. The compound of claim 2, wherein R.sup.1 is hydrogen or
CO.sub.2R.sup.11 and R.sup.11 is C.sub.1-C.sub.6 alkyl.
4. The compound of claim 2 wherein R.sup.1 is --CO.sub.2R.sup.11,
--COR.sup.12, --C(R.sup.13).sub.3, or another amine protecting
group, wherein R.sup.11 and R.sup.12 defined as in claim 1 above,
R.sup.2 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl, wherein the alkyl, alkenyl, or the alkynyl
group is optionally substituted with 1-3 substituents selected from
the group consisting of keto, halo, C.sub.1-C.sub.6 alkoxy, amino,
hydroxy, cyano, nitro, --NHCOCH.sub.3, --N.sub.3, and --CO.sub.2H
or an ester thereof, and Z.sup.3 is hydroxy or hydrogen.
5. The compound claim 1 of Formula (IIA): ##STR00029## wherein
R.sup.1, R.sup.25, and R.sup.26 are defined as in Formula (I)
above.
6. A compound of formula: ##STR00030## or a salt thereof.
7. The compound of claim 5, which is an R,R enantiomer.
8. An isolated R,R enantiomer of the compound of claim 7, which is
in substantial enantiomeric excess (ee).
9. A process for preparing a compound of Formula (II) ##STR00031##
or a salt thereof, wherein R.sup.1 is selected from the group
consisting of hydrogen, --CO.sub.2R.sup.11, --COR.sup.12,
--C(R.sup.13).sub.3 and an amine protecting group; R.sup.11 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl
optionally substituted with 1-3 substituents selected from the
group consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, --N.sub.3, hydroxy, C.sub.1-C.sub.6 alkoxy,
silyl, nitro, cyano, and CO.sub.2H or an ester thereof,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and
C.sub.3-C.sub.8 heterocyclyl, R.sup.12 and R.sup.13 independently
are selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl optionally substituted with 1-3 substituents selected from
the group consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, --N.sub.3, hydroxy, C.sub.1-C.sub.6 alkoxy,
silyl, nitro, cyano, and CO.sub.2H or an ester thereof,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and
C.sub.3-C.sub.8 heterocyclyl, the amine protecting group is
selected from the group consisting of --CO.sub.2CMe.sub.3,
--CO.sub.2Bn, --CO.sub.2-allyl, --Fmoc (flurenyloxymethyl),
--COCF.sub.3, Bn(CH.sub.2Ph), --CHPh.sub.2, and --CPh.sub.3;
R.sup.2 and R.sup.3 independently are selected from the group
consisting of --S--R.sup.21 and --OR.sup.22, or R.sup.2 and R.sup.3
together with the carbon atom to whch they are bound form a keto
(C.dbd.O) group or form a 5-6 membered cyclic ketal or thioketal of
formula: ##STR00032## each R.sup.21 is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo,
--N.sub.3, hydroxy, amino, C.sub.1-C.sub.6 alkoxy, silyl, nitro,
cyano, and CO.sub.2H or an ester thereof, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and C.sub.3-C.sub.8
heterocyclyl; each R.sup.22 is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl optionally substituted
with 1-3 substituents selected from the group consisting of
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3,
hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H
or an ester thereof, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl; X is in both occurrences are O or S; m is 1, 2, 3, or 4; n
is 1 or 2; R.sup.23 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; wherein the
cycloalkyl, heterocyclyl, aryl, or heteroaryl, is optionally
substituted with 1-3 substituents selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6
alkoxy, silyl, nitro, cyano, and CO.sub.2H or an ester thereof;
which process comprises contacting a compound of Formula (IV):
##STR00033## or a salt thereof wherein, R.sup.1, R.sup.2, and
R.sup.3 are defined as in formula (III) above, with less than 1
molar equivalent of an olefin metathesis reagent under conditions
to provide a compound of Formula (II) or a salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. 119(e)
of U.S. Provisional Application Ser. No. 61/741,798 filed Jan. 25,
2012, which is hereby incorporated by reference into this
application in its entirety.
FIELD OF THE INVENTION
[0002] This invention provides (1R,4R)
7-oxo-2-azabicyclo[2.2.2]oct-5-ene as well as derivatives thereof.
Such compounds are readily converted into pharmaceutically
important compounds containing the isoquinuclidene moiety. In one
embodiment, the 7-oxo-2-azabicyclo[2.2.2]oct-5-ene compounds of
this invention are in substantially enantiomerically enriched
forms. This invention also provides for processes for preparing
such 7-oxo-2-azabicyclo[2.2.2]oct-5-ene compounds as well as for
preparing novel intermediates used therein.
BACKGROUND OF THE INVENTION
[0003] Many pharmaceutical compounds mirror the structures of
natural products. In particular, certain aspects of the natural
product are modified in order to enhance beneficial properties
and/or to minimize detrimental properties. The portion of the
natural product which imparts some or all of the pharmaceutical
activity is referred to as a "pharmacophore". One example of a
potent pharmacophore found in nature is the structurally complex
chiral isoquinuclidene moiety which has a core structure:
##STR00001##
where
##STR00002##
denotes a non-hydrogen substituent. This structure is common in
pharmacologically active natural products, such as the Iboga
alkaloids.
[0004] Synthesizing compounds to include the isoquinuclidene
moiety, especially in a substantially enantiomerically pure form is
a challenging task. Heretofore, Iboga alkaloids, such as ibogaine,
were conventionally prepared from one of its naturally occurring
precursors such as voacangine. In turn, voacangine is obtained from
plants, whose supply is limited and where the quality of the supply
is unpredictable.
[0005] Synthesizing non-natural compounds including the
structurally complex isoquinuclidene moiety, such as those used as
pharmaceutically active agents, is also challenging. For
non-natural isoquinuclidenes as 5-HT3 ligands, see, Iriepa et al.,
Bioorg. Med. Chem. Lett. 12, 2002, 189-192. See also Glick, et al.,
U.S. Pat. No. 6,211,360 which discloses a variety of complex
compounds having a carboxyl substituted isoquinuclidene ring or a
derivative of that carboxyl substitution.
SUMMARY OF THE INVENTION
[0006] Provided herein is a novel
7-oxo-2-azabicyclo[2.2.2]oct-5-ene having 1R,4R stereochemistry and
derivatives thereof, which can be converted into substantially more
complex compounds having the isoquinuclidene moiety. In one
embodiment, these compounds (as well as their intermediates) are
provided in substantially enantiomerically pure forms so as to
provide for entry into various pharmacologically active products,
containing an isoquinuclidene moiety as found for example in 5-HT3
ligands (see, Iriepa et al., supra).
[0007] Also provided herein are processes for preparing the
7-oxo-2-azabicyclo[2.2.2]oct-5-ene derivatives, and intermediates
thereto, preferably in substantially enantiomerically enriched
forms.
BRIEF DESCRIPTION OF THE FIGURES
[0008] FIG. 1 illustrates a .sup.1H-NMR spectrum in CDCl.sub.3 of
compound 10,
##STR00003##
which is an N-protected, 5 membered cyclic ketal of R,R
7-oxo-2-azabicyclo[2.2.2]oct-5-ene.
[0009] FIG. 2 illustrates a .sup.1H-NMR spectrum in CDCl.sub.3 of
compound H,
##STR00004##
which is a 5 membered cyclic ketal of R,R
7-oxo-2-azabicyclo[2.2.2]oct-5-ene.
DETAILED DESCRIPTION OF THE INVENTION
[0010] This invention relates to 1R,4R
7-oxo-2-azabicyclo[2.2.2]oct-5-ene and derivatives thereof as well
as to processes for preparing them. Before this invention is
described in greater detail, the following terms will be
defined.
[0011] As used herein and in the appended claims, the singular
forms "a", "an", and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"a salt" includes a plurality of such salts.
Definitions
[0012] As used herein, "alkenyl" refers to hydrocarbyl groups
having from 2 to 10 carbon atoms and at least one and up to 3
carbon carbon double bonds. Examples of alkenyl include vinyl,
allyl, dimethyl allyl, and the like.
[0013] As used herein, "alkoxy" refers to --O-alkyl.
[0014] As used herein, "alkyl" refers to hydrocarbyl groups having
from 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and
still more preferably 1-4 carbon atoms. The alkyl group may contain
linear or branched carbon chains. This term is exemplified by
groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,
t-butyl, n-pentyl, n-decyl and the like.
[0015] As used herein, "alkynyl" refers to hydrocarbyl groups
having from 2 to 10 carbon atoms and at least one and up to 2
carbon carbon triple bonds. Examples of alkynyl include ethynyl,
propargyl, dimethylpropargyl, and the like.
[0016] As used herein, "amino" refers to --NR.sup.xR.sup.y wherein
each R.sup.x and R.sup.y independently is hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10
heteroaryl, and C.sub.3-C.sub.8 heterocyclyl.
[0017] As used herein, "aryl" refers to an aromatic carbocyclic
group of from 6 to 14 carbon atoms having a single ring (e.g.,
phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)
which condensed rings may or may not be aromatic (e.g.,
2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like)
provided that the point of attachment is at an aromatic carbon
atom.
[0018] As used herein, "C" refers to a group having x carbon atoms,
wherein x is an integer, for example, C.sub.4 alkyl refers to an
alkyl group having 4 carbon atoms.
[0019] As used herein, "cycloalkyl" refers to cyclic hydrocarbyl
groups of from 3 to 10 carbon atoms having single or multiple
condensed rings, which condensed rings may be aromatic or contain a
heteroatom, provided that the point of attachment is at a
cycloalkyl carbon atom. Cycloalkyl includes, by way of example,
adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the
like. Cycloalkyl rings are preferably saturated, though, cycloalkyl
rings including 1-2 carbon carbon double bonds are also
contemplated provided that the ring is not aromatic.
[0020] As used herein, "chiral Lewis acid" refers to a Lewis acid,
which is complexed with, such as, for example, covalently bound
with, a chiral compound that can bind to the Lewis acid. Such Lewis
acids include halide and alkoxides of titanium (IV), and such other
metals. Suitable chiral compounds include various diols and amino
alcohols, such as binol, taddol, and the like, and are well known
in the art.
[0021] As used herein, the term "comprising" or "comprises" is
intended to mean that the compositions and methods include the
recited elements, but not excluding others. "Consisting essentially
of" when used to define compositions and methods, shall mean
excluding other elements of any essential significance to the
combination for the stated purpose. Thus, a composition consisting
essentially of the elements as defined herein would not exclude
other materials or steps that do not materially affect the basic
and novel characteristic(s) of the claimed invention. "Consisting
of" shall mean excluding more than trace elements of other
ingredients and substantial method steps. Embodiments defined by
each of these transition terms are within the scope of this
invention.
[0022] As used herein, "ee" refers to enantiomeric excess and is
expressed as (e.sup.1-e.sup.2)% where e.sup.1 and e.sup.2 are the
two enantiomers. For example, if the % of e.sup.1 is 95 and the %
of e.sup.2 is 5, then the e.sup.1 enantiomer is present in an ee of
90%. The ee of an enantiomer in a mixture of enantiomers is
determined following various methods well known to the skilled
artisan, such as using chiral lanthanide based nuclear magnetic
resonance shift reagents, forming derivatives with chiral compounds
such as chiral hydroxyacids, amino acids, and the like. Various
physical measurements such as circular dichroism, optical rotation,
etc. are also useful in determining the ee of a mixture of
enantiomers.
[0023] As used herein, --CO.sub.2H "ester" refers to
--CO.sub.2R.sup.E wherein R.sup.E is selected from the group
consisting of C.sub.6-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl
optionally substituted with 1-3 C.sub.6-C.sub.10 aryl groups.
[0024] As used herein, "halo" refers to F, Cl, Br, or I.
[0025] As used herein, "heteroaryl" refers to an aromatic group of
from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the
group consisting of oxygen, nitrogen, sulfur within the ring,
wherein the nitrogen and/or sulfur atom(s) of the heteroaryl are
optionally oxidized (e.g., N-oxide, --S(O)-- or --S(O).sub.2--),
provided that the ring has at least 5 ring atoms and up to 14, or
preferably from 5-10, ring atoms. Such heteroaryl groups can have a
single ring (e.g., pyridyl or furyl) or multiple condensed rings
(e.g., indolizinyl or benzothienyl) wherein the condensed rings may
or may not be aromatic and/or contain a heteroatom provided that
the point of attachment is through an atom of the aromatic
heteroaryl group. Examples of heteroaryls include pyridyl,
pyrrolyl, indolyl, thiophenyl, furyl, and the like.
[0026] As used herein, "heterocyclyl" or heterocycle refers to a
cycloalkyl group of from 1 to 10 carbon atoms and 1 to 4
heteroatoms selected from the group consisting of oxygen, nitrogen,
sulfur within the ring, wherein the nitrogen and/or sulfur atom(s)
of the heteroaryl are optionally oxidized (e.g., N-oxide, --S(O)--
or --S(O).sub.2--), provided that the ring has at least 3 and up to
14, or preferably from 5-10 ring atoms. Such heterocyclyl groups
can have a single ring or multiple condensed rings wherein the
condensed rings may not contain a heteroatom and/or may contain an
aryl or a heteroaryl moiety, provided that the point of attachment
is through an atom of the non-aromatic heterocyclyl group. Examples
of heterocyclyl include pyrrolidinyl, piperadinyl, piperazinyl, and
the like. Heterocyclyl rings are preferably saturated, though,
heterocyclyl rings including 1-2 carbon carbon double bonds are
also contemplated provided that the ring is not aromatic.
[0027] As used herein, "olefin metathesis reagent" refers to well
known reagents that are employed, preferably in catalytic amounts,
for ring closing olefin metathesis, as schematically shown
below
##STR00005##
Exemplary olefin metathesis reagents include, without limitation,
various commercially available, for example from Sigma-Aldrich,
Grubbs' catalysts, such as:
##STR00006##
or their immobilized version, such as:
##STR00007##
In certain embodiments, commercially available (for example from
Strem Chemicals, Inc.) molybdenum based Schrock's catalysts, such
as:
##STR00008##
are also useful as olefin metathesis reagent.
[0028] As used herein, "protecting group" or "Pg" refers to well
known functional groups which, when bound to a functional group,
render the resulting protected functional group inert to the
reaction to be conducted on other portions of the compound and the
corresponding reaction condition, and which can be reacted to
regenerate the original functionality under deprotection
conditions. The protecting group is selected to be compatible with
the remainder of the molecule. In one embodiment, the protecting
group is an "amine protecting group" which protects an --NH-- or an
--NH.sub.2-- moiety, for example during the syntheses described
here. Examples of amine protecting groups include, for instance,
benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), Fmoc, and the
like. In another embodiment, the protecting group is a "hydroxy
protecting group" which protects a hydroxyl functionality during
the synthesis described here. Examples of hydroxyl protecting
groups include, for instance, benzyl, p-methoxybenzyl,
p-nitrobenzyl, allyl, trityl, dialkylsilylethers, such as
dimethylsilyl ether, and trialkylsilyl ethers such as
trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl
ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-,
di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl,
trichloroacetyl, trifluoroacetyl; and carbonates such as methyl,
ethyl, 2,2,2-trichloroethyl, allyl, and benzyl. Examples of keto
protecting groups include linear and cyclic ketals and Schiff's
bases. As the skilled artisan would appreciate, one or more of
these protecting groups are also useful as amine protecting groups.
Additional examples of amine, hydroxy, and keto protecting groups
are found in standard reference works such as Greene and Wuts,
Protective Groups in Organic Synthesis., 2d Ed., 1991, John Wiley
& Sons, and McOmie Protective Groups in Organic Chemistry,
1975, Plenum Press. Methods for protecting and deprotecting
hydroxyl, --NH--, --NH.sub.2--, and keto groups disclosed herein
can be found in the art, and specifically in Greene and Wuts,
supra, and the references cited therein.
[0029] As used herein, "silyl" refers to Si(R.sup.z).sub.3 wherein
each R.sup.z independently is C.sub.1-C.sub.6 alkyl or
C.sub.6-C.sub.10 aryl.
[0030] As used herein, "substantially enantiomerically enriched,"
"substantially enantiomerically pure" and grammatical equivalents
thereof refers to an enantiomer in an enantiomeric mixture with at
least 95% ee, preferably 98% ee, or more preferably 99% ee.
Compounds of the Invention
[0031] In one aspect, this invention provides a compound of Formula
(I) or (Ia):
##STR00009##
[0032] or a salt thereof wherein,
[0033] R.sup.1 is selected from the group consisting of hydrogen,
--CO.sub.2R.sup.11, --COR.sup.12, --C(R.sup.13).sub.3, and another
amine protecting group;
[0034] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1-3 substituents
selected from the group consisting of C.sub.6-C.sub.10 aryl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10 heteroaryl,
C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3, hydroxy,
C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H or an
ester thereof, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
cycloalkyl, and C.sub.3-C.sub.8 heterocyclyl;
[0035] R.sup.12 and R.sup.13 independently are selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo,
amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro,
cyano, and CO.sub.2H or an ester thereof, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and C.sub.3-C.sub.8
heterocyclyl;
[0036] R.sup.2 and R.sup.3 independently are selected from the
group consisting of hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl, --SR.sup.21
and --OR.sup.22, wherein the alkyl, alkenyl, or the alkynyl group
is optionally substituted with 1-3 substituents selected from the
group consisting of keto, halo, C.sub.1-C.sub.6 alkoxy, amino,
hydroxy, cyano, nitro, --NHCOCH.sub.3, --N.sub.3, and --CO.sub.2H
or an ester thereof, provided that at least one of R.sup.2 and
R.sup.3, preferably R.sup.2 is a non-hydrogen substituent, or
[0037] R.sup.2 and R.sup.3 together with the carbon atom to which
they are bonded to form a keto (C.dbd.O) group, a Schiff base
(.dbd.NR.sup.24), a vinylidene moiety of formula .dbd.CR.sup.25
R.sup.26, or form a 5-6 membered cyclic ketal or thioketal, which
cyclic ketal or thioketal is of formula:
##STR00010##
[0038] each R.sup.21 is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
substituents selected from the group consisting of C.sub.6-C.sub.10
aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10 heteroaryl,
C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3, hydroxy,
C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H or an
ester thereof, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
cycloalkyl, and C.sub.3-C.sub.8 heterocyclyl;
[0039] each R.sup.22 is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
substituents selected from the group consisting of C.sub.6-C.sub.10
aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10 heteroaryl,
C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3, hydroxy,
C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H or an
ester thereof, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl;
[0040] where X in both occurrences is either oxygen or sulfur;
[0041] m is 1, 2, 3, or 4;
[0042] n is 1 or 2;
[0043] R.sup.23 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl;
[0044] R.sup.24 is selected from the group consisting of
C.sub.6-C.sub.10 aryl and C.sub.2-C.sub.10 heteroaryl;
[0045] R.sup.25 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl, wherein the alkyl, alkenyl,
or the alkynyl group is optionally substituted with 1-3
substituents selected from the group consisting of keto,
C.sub.1-C.sub.6 alkoxy, amino, hydroxy, cyano, nitro,
--NHCOCH.sub.3, and --CO.sub.2H or an ester thereof;
[0046] R.sup.26 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0047] R.sup.4 and R.sup.5 independently are selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.6 alkyl
optionally substituted with 1-3 substituents selected from
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3,
hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, vinyl,
ethynyl, and CO.sub.2H or an ester thereof,
[0048] R.sup.6 is selected from the group consisting of --O--,
--NH--, and --NR.sup.61;
[0049] R.sup.61 is selected from the group consisting of hydrogen,
--SO.sub.2R.sup.62, and an amine protecting group;
[0050] R.sup.62 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 2-5 halo groups
and C6-C10 areyl optionally substituted with 1-3 C.sub.1-C.sub.6
alkyl and halo groups;
[0051] the amine protecting group is selected from the group
consisting of --CO.sub.2CMe.sub.3, --CO.sub.2Bn, --CO.sub.2-allyl,
--Fmoc (flurenyloxymethyl), --COCF.sub.3, Bn(CH.sub.2Ph),
--CHPh.sub.2, and --CPh.sub.3; and
[0052] wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl,
is optionally substituted with 1-3 substituents selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6
alkoxy, silyl, nitro, cyano, and CO.sub.2H or an ester thereof.
[0053] As used herein, a salt refers to preferably a salt of a
mineral acid, or an organic acid such as a carboxylic acid or a
sulfonic acid, and/or to alkali, alkaline earth, and various
ammonium (including tetraalkyl ammonium, pyridinum, imidazolium and
the like) salts. Non limiting examples of acid salts include salts
of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid, methane sulfonic acid, phosphorous acid, nitric acid,
perchloric acid, acetic acid, tartaric acid, lactic acid, succinic
acid, and citric acid.
[0054] As used herein, compounds of this invention include
tautomers thereof, including without limitation, keto enol,
--NH--CO-- --N.dbd.COH--, and such other tautomers.
[0055] In another embodiment, the compound is of Formula (II):
##STR00011##
wherein R.sup.1, R.sup.2, and R.sup.3 are defined as in Formula (I)
above.
[0056] For the compound of Formula (II), in a preferred embodiment,
CR.sup.2R.sup.3 is a protected ketone, more preferably, a cyclic
ketal or thioketal. Within these embodiments, in a preferred
embodiment, R.sup.1 is hydrogen.
[0057] In another embodiment, the compound is of formula (II):
##STR00012##
wherein R.sup.1 is --CO.sub.2R.sup.11, --COR.sup.12,
--C(R.sup.13).sub.3, or another amine protecting group. In another
embodiment, R.sup.11 and R.sup.12 are independently methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, or tertiary butyl. In another
embodiment, R.sup.2 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, wherein the alkyl, alkenyl, or
the alkynyl group is optionally substituted with 1-3 substituents
selected from the group consisting of keto, halo, C.sub.1-C.sub.6
alkoxy, amino, hydroxy, cyano, nitro, --NHCOCH.sub.3, --N.sub.3,
and --CO.sub.2H or an ester thereof. In another embodiment, R.sup.3
is hydroxy. In another embodiment, R.sup.3 is hydrogen.
[0058] In another embodiment, the compound is of Formula (IIA):
##STR00013##
wherein R.sup.1, R.sup.25, and R.sup.26 are defined as in Formula
(I) above. In another embodiment, R.sup.1 is --CO.sub.2R.sup.11,
--COR.sup.12, --C(R.sup.13).sub.3, and another amine protecting
group. In another embodiment, R.sup.11 and R.sup.12 are
independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or
tertiary butyl. In another embodiment, R.sup.25 is C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl,
wherein the alkyl, alkenyl, or the alkynyl group is optionally
substituted with 1-3 substituents selected from the group
consisting of keto, C.sub.1-C.sub.6 alkoxy, amino, hydroxy, cyano,
nitro, --NHCOCH.sub.3, and --CO.sub.2H or an ester thereof. In one
embodiment, R.sup.26 is hydrogen.
[0059] In another embodiment, the compound is of Formula (III):
##STR00014##
wherein R.sup.1 is defined as in Formula (I) above, and is
preferably a non-hydrogen substituent. In another embodiment, for
the compound of Formula (III), R.sup.1 is CO.sub.2R.sup.11 or
another amine protecting group as defined herein, and R.sup.11 is
C.sub.1-C.sub.6 alkyl.
[0060] In another embodiment, this invention provides compounds of
the formula:
##STR00015##
or a salt thereof. In another embodiment, the compound is an R,R
enantiomer. In another embodiment, the compound is in substantial
enantiomeric excess (ee).
Processes of the Invention
[0061] The compounds of this invention are prepared following novel
processes provided herein and obvious modifications of synthetic
methods well known to the skilled artisan upon appropriate
substitution of starting material and reagents, and/or following
methods that will become apparent to the skilled artisan upon
reading this disclosure.
[0062] Accordingly, the compounds of this invention can be prepared
from readily available starting materials using the general
processes and procedures described and illustrated herein. Optimum
reaction conditions may vary with the particular reactants or
solvent used, but such conditions can be determined by one skilled
in the art by routine optimization procedures.
[0063] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions.
Suitable protecting groups for various functional groups as well as
suitable conditions for protecting and deprotecting particular
functional groups are well known in the art. For example, numerous
protecting groups are described in T. W. Greene and G. M. Wuts,
Protecting Groups in Organic Synthesis, Third Edition, Wiley, New
York, 1999, and references cited therein.
[0064] The starting materials for the following reactions are
generally known compounds or can be prepared by known procedures or
obvious modifications thereof. For example, many of the starting
materials are available from commercial suppliers such as Aldrich
Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif.,
USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be
prepared by procedures, or obvious modifications thereof, described
in standard reference texts such as Fieser and Fieser's Reagents
for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991),
Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals
(Elsevier Science Publishers, 1989), Organic Reactions, Volumes
1-40 (John Wiley and Sons, 1991), March's Advanced Organic
Chemistry, (John Wiley and Sons, 4.sup.th Edition), and Larock's
Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
In one of its process aspects, this invention provides a process
for preparing a compound of Formula (II)
##STR00016##
or a salt thereof, wherein R.sup.1, R.sup.2, and R.sup.3 are
defined as in Formula (I) or in any aspect or embodiment here,
which process comprises contacting a compound of Formula (IV):
##STR00017##
or a salt thereof with from 0.1-10 molar equivalent, preferably
less than 1 molar equivalent of an olefin metathesis reagent under
conditions to provide the compound of Formula (II) or a salt
thereof.
[0065] Such conditions include the use of a suitable inert solvent,
such as for example chlorinated solvent such as dichloromethane, a
temperature of from 15.degree. C. to 40.degree. C., and reaction
times of from 0.5 h to 1 day. Preferably, the reaction is carried
out for a period of time sufficient to provide a substantial amount
of the product, which can be ascertained by using routine methods
such as thin layer chromatography, .sup.1H-nuclear magnetic
resonance (NMR) spectroscopy, and the likes. The products can be
isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization,
precipitation, and distillation under reduced pressure, or the
products may be used for a subsequent reaction without further
purification.
[0066] The synthesis of the compounds of this invention following
the processes of this invention are schematically shown below.
##STR00018##
The first step of the process uses, as the chiral element, D-serine
methyl ester (2), which is reacted with triphosgene or another
phosgene source, in the presence of a base, and further with an
allylating agent and another base, preferably a hydride, to provide
(R)-2-oxo oxazolidine-4-carboxylic acid methyl ester (3).
Preferably the reactions are carried out in a solvent that is inert
to the reactant and reagents. The use of an immobilized,
resin-bound via the carboxyl moiety-serine ester is also
contemplated as the starting material to reduce potential product
loss during aqueous work up. The N-allylation, introduces one of
the requisite alkenes (3) to the molecule.
[0067] The second alkene results from the Weinreb amide procedure
to yield the vinyl ketone (5). Accordingly, compound 3 is
hydrolyzed using aqueous alkali and converted to its N-methoxy
amide (4). Compound 4 is reacted with a vinyl anion equivalent,
such as vinyl magnesium bromide, in a solvent such as ether or
tetrahydrofuran, preferably at a temperature of -5-10.degree. C. to
provide compound 5.
[0068] The first Grubbs reaction on 5 affords the chiral
oxazolidinone (6). Conjugate addition of vinyl magnesium bromide in
presence of a copper (I) salt such as CuI, protection of the keto
group, alkaline oxazolidine ring cleavage, alkylation or acylation
with R.sup.1-L, where L is a leaving group, such as e.g. a halo or
a mesylate, tosylate, or such other group, provides compound V.
Compound V is selectively oxidized to an aldehyde to provide
compound VI. Various art known oxidative methods including
pyridinium chlorochromate, Swern oxidation, N-methyl morphomine
--N-oxide (NMO) and perruthenate, are useful for the selective
oxidation. Olefination of compound VI using Tebbe's reagent or a
Wittig reaction yields the 1,5 divinyl substituted piperidine (IV).
Grubbs cyclization of compound IV yields compound II. When R.sup.1
is hydrogen, and CR.sup.2R.sup.3 is:
##STR00019##
the .sup.1H-NMR of the resulting compound, compound 10, is shown in
FIG. 1.
[0069] Compounds of Formulas (IIIA) and (IIIB) are synthesized from
a compound of formula (II) wherein CR.sup.2R.sup.3 is keto
following a reaction, e.g., with an alkyl anion (R.sup.2(-)) or
with a Wittig reagent (Ph.sub.3P.dbd.CR.sup.25R.sup.26), as are
well known to the skilled artisan. The compound wherein R.sup.3 is
OH is converted to one wherein R.sup.3 is hydrogen by well known
reaction such as by dehydration-hydrogenation. As to the compounds
where CR.sup.2R.sup.3 is C.dbd.CR.sup.25R.sup.26, they can be
hydrogenated employing catalytic hydrogenation procedures well
known to the skilled artisan such that the hydrogenation occurs
from the alpha or the bottom face and provides compounds where
R.sup.3 is hydrogen.
[0070] Compounds of Formula (II) can be further elaborated as shown
below:
##STR00020##
Methods of epoxidation and aziridination of double bounds are well
known to the skilled artisan, and are performed, for example, with
peracids such as percarboxylic acids, and for example, using
p-toluene sulfonamide (TsNH.sub.2) and an oxidant. Aziridines or
protected aziridines, such as those provided herein, are also
prepared by multi-step methods by first forming a geminal amino
alcohol, protecting the amine, converting the alcohol to a leaving
group (see supra), deprotecting the amine protection and cyclizing
to form an aziridine which can be protected following methods well
known to the skilled artisan.
[0071] More specifically, compound 6 is converted to compound 1 as
illustrated schematically below:
##STR00021##
Conjugate addition of vinyl magnesium bromide, oxazolidine ring
cleavage, and keto group protection provides compound 7. Compound 7
is oxidized using NMO and tetrapropylammonium perruthenate to
provides compound 8. Olefination of 8 yields the 1,5 divinyl
substrate piperidine (9). Grubbs cyclization of 9 yields optically
active (10) which is the carbonyl group and N-- protected
derivative of the 1R,4R -2-azabicyclo[2,2,2]oct-5-ene-7-one (1)
mentioned above. The .sup.1H-NMR of compound 10 is provided in FIG.
1. Deprotection of the N-- protecting groups of 10 provide compound
11, whose NMR is provided in FIG. 2. Deprotection of the carbonyl
protection of 10 provides compound 1.
[0072] The isoquinuclidene compounds provided herein are also
synthesized utilizing Diels
[0073] Alder reactions as illustrated schematically below:
##STR00022##
A Diels Alder reaction between compound VII, which is readily
available, and acrolein, in presence of chiral catalysts, such as
chiral Lewis acid catalysts provides compound VIII. In preferred
embodiments, compound VIII is obtained in >99% ee. The aldehyde
group in compound VIII is oxidized, following various well known
methods, to a carboxylic acid and esterified to provide a carboxyl
ester such as a methyl ester. Compound IX is decarboxylated by
reacting with nitrosobenzene in presence of a base (such as, for
example, hindered amide and silazide bases well known in the art)
to provide Schiff's base X. Compound X is hydrolyzed to provide
compound III. Compound III is conveniently elaborated to other
compounds of this invention as shown above.
[0074] More specifically, a compound of this invention, compound
15, is synthesized as illustrated schematically below:
##STR00023##
N-carbomethoxy-1,2-dihydropyridine is used as a starting material.
Hypochlorite and 2-methyl-2-butene is used for oxidizing the --CHO
group to a --CO.sub.2H group.
[0075] Alternatively, compound III is synthesized using an
acrylamide containing a chiral auxiliary as illustrated
schematically below:
##STR00024##
Various chiral auxiliaries useful for this purpose are well known
in the art and the camphor based auxiliary is shown solely for
illustration. In preferred embodiments, compound XI is obtained in
>99% ee. Preferably, R.sup.1 is a non-hydrogen substituent as
defined herein.
[0076] More specifically, a compound of this invention, compound
15, is synthesized using N-carbomethoxy-1,2-dihydropyridine as a
starting material and TiCl.sub.4 as the Lewis acid catalyst as
illustrated schematically below:
##STR00025##
[0077] The reactions are carried out, preferably in an inert
solvent that will be apparent to the skilled artisan upon reading
this disclosure, for a period of time sufficient to provide a
substantial amount of the product, which can be ascertained by
using routine methods such as thin layer chromatography,
.sup.1H-nuclear magnetic resonance (NMR) spectroscopy, and the
likes. The products can be isolated and optionally purified using
standard purification techniques, such as liquid chromatography,
crystallization, precipitation, and distillation under reduced
pressure, or the products may be used for a subsequent reaction
without further purification.
UTILITY
[0078] The compounds and processes provided herein have utility in
synthesizing pharmaceutically active isoquinuclidene derivatives
described for example in U.S. Pat. No. 6,211,360 and in
synthesizing non-natural isoquinuclidene derivatives useful as
5-HT3 ligands (see, Iriepa et al., supra).
* * * * *